Hydroxymethylglutaryl-coenzyme A reductase inhibitor: Difference between revisions

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===Patients with normal LDL cholesterol levels===
===Patients with normal LDL cholesterol levels===
Statin therapy benefited about 1 of every 170 patients with [[LDL cholesterol]] less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity [[C-reactive protein]] levels of 2.0 mg per liter or higher who took [[rosuvastatin]] 20 mg daily for 2 years if they are similar to the patients in the JUPITER [[randomized controlled trial]] ([[number needed to treat]] for two years is 170).<ref name="pmid18997196">{{cite journal |author=Ridker PM, Danielson E, Fonseca FA, ''et al'' |title=Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=November |pmid=18997196 |doi=10.1056/NEJMoa0807646 |url= |issn=}}</ref><ref name="pmid14609996">{{cite journal |author=Ridker PM |title=Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial |journal=Circulation |volume=108 |issue=19 |pages=2292–7 |year=2003 |month=November |pmid=14609996 |doi=10.1161/01.CIR.0000100688.17280.E6 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=14609996 |issn=}}</ref> The frequency of death from any cause fell from 2.8% to 2.2% ([[number needed to treat]] for two years is 180). However, this trial was stopped early afer an interim analysis so it is likely that the result is exaggerated.
Statin therapy benefited about 1 of every 170 patients with [[LDL cholesterol]] less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity [[C-reactive protein]] levels of 2.0 mg per liter or higher who took [[rosuvastatin]] 20 mg daily for 2 years if they are similar to the patients in the JUPITER [[randomized controlled trial]] ([[number needed to treat]] for two years is 170).<ref name="pmid18997196">{{cite journal |author=Ridker PM, Danielson E, Fonseca FA, ''et al'' |title=Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=November |pmid=18997196 |doi=10.1056/NEJMoa0807646 |url= |issn=}}</ref><ref name="pmid14609996">{{cite journal |author=Ridker PM |title=Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial |journal=Circulation |volume=108 |issue=19 |pages=2292–7 |year=2003 |month=November |pmid=14609996 |doi=10.1161/01.CIR.0000100688.17280.E6 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=14609996 |issn=}}</ref> The frequency of death from any cause fell from 2.8% to 2.2% ([[number needed to treat]] for two years is 180). However, this trial was stopped early after an interim analysis so it is likely that the result is exaggerated.


[[Rosuvastatin]] may also prevent venous [[embolism and thrombosis]].<ref name="pmid19329822">{{cite journal| author=Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al.| title=A randomized trial of rosuvastatin in the prevention of venous thromboembolism. | journal=N Engl J Med | year= 2009 | volume= 360 | issue= 18 | pages= 1851-61 | pmid=19329822  
[[Rosuvastatin]] may also prevent venous [[embolism and thrombosis]].<ref name="pmid19329822">{{cite journal| author=Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al.| title=A randomized trial of rosuvastatin in the prevention of venous thromboembolism. | journal=N Engl J Med | year= 2009 | volume= 360 | issue= 18 | pages= 1851-61 | pmid=19329822  
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19329822 | doi=10.1056/NEJMoa0900241 | pmc=PMC2710995 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19755356 Review in: Ann Intern Med. 2009 Sep 15;151(6):JC3-10] <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19329822 | doi=10.1056/NEJMoa0900241 | pmc=PMC2710995 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19755356 Review in: Ann Intern Med. 2009 Sep 15;151(6):JC3-10]</ref>
 
==Adverse effects==
Drug toxicity is more likely to happen when statins are given with patients who are also taking inhibitors of the [[cytochrome P-450]] isoenzyme 3A4.<ref name="pmid23778904">{{cite journal| author=Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M et al.| title=Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. | journal=Ann Intern Med | year= 2013 | volume= 158 | issue= 12 | pages= 869-76 | pmid=23778904 | doi=10.7326/0003-4819-158-12-201306180-00004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23778904  }} </ref> Examples are the macrolide [[antimicrobial]]s clarithromycin or erythromycin (but not azithromycin).
 
===Myopathy===
Approximately 10% of patients stop statins due to muscular symptoms.<ref name="pmid23546564">{{cite journal| author=Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M et al.| title=Discontinuation of statins in routine care settings: a cohort study. | journal=Ann Intern Med | year= 2013 | volume= 158 | issue= 7 | pages= 526-34 | pmid=23546564 | doi=10.7326/0003-4819-158-7-201304020-00004 | pmc=PMC3692286 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23546564  }} </ref> However, most of these patients can resume a statin, especially if a different statin is used.<ref name="pmid23546564">{{cite journal| author=Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M et al.| title=Discontinuation of statins in routine care settings: a cohort study. | journal=Ann Intern Med | year= 2013 | volume= 158 | issue= 7 | pages= 526-34 | pmid=23546564 | doi=10.7326/0003-4819-158-7-201304020-00004 | pmc=PMC3692286 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23546564  }} </ref>
 
===Hematological===
Mild [[thrombocytopenia]] has been reported.<ref name="pmid18386006">{{cite journal| author=Ames PR| title=Simvastatin-induced thrombocytopaenia: a further case and a brief on its clinical relevance. | journal=Ann Hematol | year= 2008 | volume= 87 | issue= 9 | pages= 773-4 | pmid=18386006
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18386006 | doi=10.1007/s00277-008-0480-1 }}</ref><ref name="pmid9788465">{{cite journal| author=González-Ponte ML, González-Ruiz M, Duvós E, Gutiérrez-Iñiguez MA, Olalla JI, Conde E| title=Atorvastatin-induced severe thrombocytopenia. | journal=Lancet | year= 1998 | volume= 352 | issue= 9136 | pages= 1284 | pmid=9788465
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9788465 | doi=10.1016/S0140-6736(05)70491-8 }}</ref><ref name="pmid9788466">{{cite journal| author=McCarthy LJ, Porcu P, Fausel CA, Sweeney CJ, Danielson CF| title=Thrombotic thrombocytopenic purpura and simvastatin. | journal=Lancet | year= 1998 | volume= 352 | issue= 9136 | pages= 1284-5 | pmid=9788466
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9788466 | doi=10.1016/S0140-6736(05)70492-X }}</ref> One [[cohort study]] reported that 8% of patients developed thrombocytopenia while taking [[simvastatin]].<ref name="pmid8039527">{{cite journal| author=Miserez AR, Rossi FA, Keller U| title=Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects. | journal=Eur J Clin Pharmacol | year= 1994 | volume= 46 | issue= 2 | pages= 107-14 | pmid=8039527
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8039527 }} </ref>
 
===Diabetes===
Statins may<ref name="pmid21693744">{{cite journal| author=Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD et al.| title=Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. | journal=JAMA | year= 2011 | volume= 305 | issue= 24 | pages= 2556-64 | pmid=21693744 | doi=10.1001/jama.2011.860 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21693744  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22007066 Review in: Ann Intern Med. 2011 Oct 18;155(8):JC4-7] </ref><ref name="pmid20167359">{{cite journal| author=Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al.| title=Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. | journal=Lancet | year= 2010 | volume= 375 | issue= 9716 | pages= 735-42 | pmid=20167359 | doi=10.1016/S0140-6736(09)61965-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20167359  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20547901 Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-7]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20522688 Review in: Evid Based Med. 2010 Jun;15(3):84-5] </ref> or may not<ref name="pmid21989464">{{cite journal| author=Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B et al.| title=Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. | journal=CMAJ | year= 2011 | volume= 183 | issue= 16 | pages= E1189-202 | pmid=21989464 | doi=10.1503/cmaj.101280 | pmc=PMC3216447 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21989464  }} </ref> increase [[diabetes]] according to meta-analyses:
*A [[meta-analysis]] of five [[randomized controlled trial]]s that compared high and low doses of statins among 32,752 subjects ''with'' [[coronary artery disease]] found a [[statistical significance|significantly]] increased [[odds ratio]] of 1.12 (95% [[confidence interval|CI]], 1.04-1.22; I(2) = 0%)<ref name="pmid21693744">{{cite journal| author=Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD et al.| title=Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. | journal=JAMA | year= 2011 | volume= 305 | issue= 24 | pages= 2556-64 | pmid=21693744 | doi=10.1001/jama.2011.860 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21693744  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22007066 Review in: Ann Intern Med. 2011 Oct 18;155(8):JC4-7] </ref>
*A [[meta-analysis]] of  13 [[randomized controlled trial]]s that compared statins to no statins among 91,140 subjects (with and without [[coronary artery disease]]), found a [[statistical significance|significantly]] increased [[odds ratio]] of 1.09 (95% [[confidence interval|CI]], 1.02-1.17; I(2) = 11%) <ref name="pmid20167359">{{cite journal| author=Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al.| title=Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. | journal=Lancet | year= 2010 | volume= 375 | issue= 9716 | pages= 735-42 | pmid=20167359 | doi=10.1016/S0140-6736(09)61965-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20167359  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20547901 Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-7]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20522688 Review in: Evid Based Med. 2010 Jun;15(3):84-5] </ref>
*A [[meta-analysis]] of four [[randomized controlled trial]]s with 31,818 subjects ''without'' [[coronary artery disease]] found an insignificantly increased [[relative risk]] of 1.05 (95% [[confidence interval|CI]], 0.84–1.32)<ref name="pmid21989464">{{cite journal| author=Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B et al.| title=Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. | journal=CMAJ | year= 2011 | volume= 183 | issue= 16 | pages= E1189-202 | pmid=21989464 | doi=10.1503/cmaj.101280 | pmc=PMC3216447 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21989464  }} </ref>


==References==
==References==
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<references/>[[Category:Suggestion Bot Tag]]

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Hydroxymethylglutaryl-coenzyme A reductase inhibitors, also called statins, are antilipemic agents "that inhibit HMG-CoA reductases, which reduce the chemical 3-hydroxy-3-methyl-glutaryl CoA. They have been shown to directly lower cholesterol synthesis.[1]

Classification

The following classification has been proposed based on molecular structure:[2][3]

Type 1

Type 1 statins (e.g., mevastatin, lovastatin, pravastatin, simvastatin) bind to HMG-CoA reductase using a decalin ring.

Type 2

Type 2 statins (e.g., fluvastatin, cerivastatin, atorvastatin, and rosuvastatin) bind to HMG-CoA reductase using a fluorophenyl group.

Effectiveness

Statins can help in the primary prevention of coronary heart disease among patients at risk.[4]

Diabetic patients

Statin therapy benefited about 1 of every 24 diabetic patients who used the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (number needed to treat is 24).[5]

Patients with average LDL cholesterol levels

Statin therapy benefited about 1 of every 24 patients with LDL cholesterol that averaged 150 mg per deciliter who took lovastatin 20-40 mg daily for 5 years if they are similar to the patients in the AFCAPS/TexCAPS randomized controlled trial (number needed to treat is 24).[6]

Patients with normal LDL cholesterol levels

Statin therapy benefited about 1 of every 170 patients with LDL cholesterol less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher who took rosuvastatin 20 mg daily for 2 years if they are similar to the patients in the JUPITER randomized controlled trial (number needed to treat for two years is 170).[7][8] The frequency of death from any cause fell from 2.8% to 2.2% (number needed to treat for two years is 180). However, this trial was stopped early after an interim analysis so it is likely that the result is exaggerated.

Rosuvastatin may also prevent venous embolism and thrombosis.[9]

Adverse effects

Drug toxicity is more likely to happen when statins are given with patients who are also taking inhibitors of the cytochrome P-450 isoenzyme 3A4.[10] Examples are the macrolide antimicrobials clarithromycin or erythromycin (but not azithromycin).

Myopathy

Approximately 10% of patients stop statins due to muscular symptoms.[11] However, most of these patients can resume a statin, especially if a different statin is used.[11]

Hematological

Mild thrombocytopenia has been reported.[12][13][14] One cohort study reported that 8% of patients developed thrombocytopenia while taking simvastatin.[15]

Diabetes

Statins may[16][17] or may not[18] increase diabetes according to meta-analyses:

References

  1. ↑ Anonymous. Hydroxymethylglutaryl-coenzyme A reductase inhibitors. National Library of Medicine. Retrieved on 2008-01-18.
  2. ↑ Istvan ES, Deisenhofer J (2001). "Structural mechanism for statin inhibition of HMG-CoA reductase". Science 292 (5519): 1160–4. DOI:10.1126/science.1059344. PMID 11349148. Research Blogging.
  3. ↑ Istvan E (2003). "Statin inhibition of HMG-CoA reductase: a 3-dimensional view". Atheroscler Suppl 4 (1): 3–8. PMID 12714031. [e]
  4. ↑ Brugts JJ, Yetgin T, Hoeks SE, et al. (2009). "The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials". BMJ 338: b2376. PMID 19567909. [e]
  5. ↑ Kearney PM, Blackwell L, Collins R, et al (2008). "Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis". Lancet 371 (9607): 117–25. DOI:10.1016/S0140-6736(08)60104-X. PMID 18191683. Research Blogging.
  6. ↑ Downs JR, Clearfield M, Weis S, et al (May 1998). "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study". JAMA 279 (20): 1615–22. PMID 9613910. [e]
  7. ↑ Ridker PM, Danielson E, Fonseca FA, et al (November 2008). "Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein". N. Engl. J. Med.. DOI:10.1056/NEJMoa0807646. PMID 18997196. Research Blogging.
  8. ↑ Ridker PM (November 2003). "Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial". Circulation 108 (19): 2292–7. DOI:10.1161/01.CIR.0000100688.17280.E6. PMID 14609996. Research Blogging.
  9. ↑ Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al. (2009). "A randomized trial of rosuvastatin in the prevention of venous thromboembolism.". N Engl J Med 360 (18): 1851-61. DOI:10.1056/NEJMoa0900241. PMID 19329822. PMC PMC2710995. Research Blogging. Review in: Ann Intern Med. 2009 Sep 15;151(6):JC3-10
  10. ↑ Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M et al. (2013). "Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study.". Ann Intern Med 158 (12): 869-76. DOI:10.7326/0003-4819-158-12-201306180-00004. PMID 23778904. Research Blogging.
  11. ↑ 11.0 11.1 Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M et al. (2013). "Discontinuation of statins in routine care settings: a cohort study.". Ann Intern Med 158 (7): 526-34. DOI:10.7326/0003-4819-158-7-201304020-00004. PMID 23546564. PMC PMC3692286. Research Blogging.
  12. ↑ Ames PR (2008). "Simvastatin-induced thrombocytopaenia: a further case and a brief on its clinical relevance.". Ann Hematol 87 (9): 773-4. DOI:10.1007/s00277-008-0480-1. PMID 18386006. Research Blogging.
  13. ↑ González-Ponte ML, González-Ruiz M, Duvós E, Gutiérrez-Iñiguez MA, Olalla JI, Conde E (1998). "Atorvastatin-induced severe thrombocytopenia.". Lancet 352 (9136): 1284. DOI:10.1016/S0140-6736(05)70491-8. PMID 9788465. Research Blogging.
  14. ↑ McCarthy LJ, Porcu P, Fausel CA, Sweeney CJ, Danielson CF (1998). "Thrombotic thrombocytopenic purpura and simvastatin.". Lancet 352 (9136): 1284-5. DOI:10.1016/S0140-6736(05)70492-X. PMID 9788466. Research Blogging.
  15. ↑ Miserez AR, Rossi FA, Keller U (1994). "Prediction of the therapeutic response to simvastatin by pretreatment lipid concentrations in 2082 subjects.". Eur J Clin Pharmacol 46 (2): 107-14. PMID 8039527.
  16. ↑ 16.0 16.1 Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD et al. (2011). "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.". JAMA 305 (24): 2556-64. DOI:10.1001/jama.2011.860. PMID 21693744. Research Blogging. Review in: Ann Intern Med. 2011 Oct 18;155(8):JC4-7
  17. ↑ 17.0 17.1 Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ et al. (2010). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.". Lancet 375 (9716): 735-42. DOI:10.1016/S0140-6736(09)61965-6. PMID 20167359. Research Blogging. Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-7 Review in: Evid Based Med. 2010 Jun;15(3):84-5
  18. ↑ 18.0 18.1 Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B et al. (2011). "Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis.". CMAJ 183 (16): E1189-202. DOI:10.1503/cmaj.101280. PMID 21989464. PMC PMC3216447. Research Blogging.
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